Dixdc1 Is a Critical Regulator of DISC1 and Embryonic Cortical Development

作者：Singh Karun K; Ge Xuecai; Mao Yingwei; Drane Laurel; Meletis Konstantinos; Samuels Benjamin A; Tsai Li Huei^*

来源：Neuron, 2010, 67(1): 33-48.

DOI：10.1016/j.neuron.2010.06.002

The psychiatric illness risk gene Disrupted in Schizophrenia-1 (DISC1) plays an important role in brain development; however, it is unclear how DISC1 is regulated during cortical development. Here, we report that DISC1 is regulated during embryonic neural progenitor proliferation and neuronal migration through an interaction with DIX domain containing-1 (Dixdc1), the third mammalian gene discovered to contain a Disheveled-Axin (DIX) domain. We determined that Dixdc1 functionally interacts with DISC1 to regulate neural progenitor proliferation by comodulating Wnt-GSK3 beta/beta-catenin signaling. However, DISC1 and Dixdc1 do not regulate migration via this pathway. During neuronal migration, we discovered that phosphorylation of Dixdc1 by cyclin-dependent kinase 5 (Cdk5) facilitates its interaction with the DISC1-binding partner Ndel1. Furthermore, Dixdc1 phosphorylation and its interaction with DISCI 1/Ndel1 in vivo is required for neuronal migration. Together, these data reveal that Dixdc1 integrates DISCI into Wnt-GSK beta/beta-catenin-dependent and -independent signaling pathways during cortical development and further delineate how DISC1 contributes to neuropsychiatric disorders.

• 出版日期2010-7-15